EP4124361B1 - Macrocyclic ligands with picolinate group(s), complexes thereof and medical uses thereof - Google Patents

Description

The present invention relates to new macrocyclic ligands as well as their complexes, in particular radioactive ones, and their uses in medical imaging and/or therapy, in particular in interventional radiology.

The present invention also relates to a new process for preparing ligands such as according to the invention, as well as their preparation intermediates.

The need for targeted and personalized treatments in oncology leads to the development of new therapeutic strategies based on early detection tools associated with more specific and more effective vectorized treatments.

Interventional radiology is a very promising area of individualized medicine. It makes it possible to combine in the same sequence a precise diagnosis of the lesion or tumor and/or its instantaneous treatment, guided and controlled by the image. It is described as a minimally invasive surgery and can therefore be performed on an outpatient basis, which saves many expensive hospital days for an effectiveness often comparable to conventional surgery. Interventional radiology can therefore represent an alternative or complement to conventional surgical treatment.

Interventional radiology allows access to a lesion or tumor located inside the body to carry out a diagnostic procedure (sampling for example) or therapeutic procedure. Imaging by fluoroscopy, ultrasound, scanner or MRI allows optimal identification, guidance and control of the medical procedure.

There is therefore a need for new molecules that can be used in medical imaging and/or therapy, in particular in interventional radiology. More particularly, there is a need for ligands making it possible to complex chemical elements, in particular metals, so as to obtain complexes which can be used in medical imaging and/or therapy, in particular in interventional radiology.

Such ligands must in particular be stable in human serum and complex sufficiently strongly with the metals so that they reach their target and do not diffuse into other organs or sensitive tissues such as bones, lungs and kidneys.

The present invention aims to provide new ligands making it possible to complex chemical elements, in particular radioelements.

The present invention also aims to provide new complexes, in particular radioactive complexes.

The present invention aims to provide ligands and/or complexes that are particularly useful in medical imaging and/or therapy, particularly in the treatment of cancers.

The present invention also aims to provide a pharmaceutical composition comprising complexes allowing medical imaging, targeting and/or treatment of cancers.

The present invention aims to provide a new process for preparing these ligands.

Starting from the work described in WO 2017/109217 and in Le Fur et al. (Inorganic Chemistry Volume: 57 Issue: 4 Pages: 2051-2063 2018 ), the inventors have developed new ligands with high affinity for certain metals, notably rare earths, very stable complexes with significant kinetic inertia. In addition, these complexes can be easily radiolabeled and then have satisfactory radiochemical yield and radiochemical purity. These complexes can also be incorporated into an iodized oil in a stable manner and with good reproducibility, and thus present a biodistribution profile allowing their use in the treatment of cancer.

dans laquelle R est un groupement de formule (II) suivante:

        -CΞC-Ph-L1-(CH2)n-L2     (II)

avec

• L1 représentant Ph ou -CΞC- ou CH2,
• L2 représentant H ou Ph ou alkylphényle,
• n compris entre 4 et 12,

ou l'un de ses sels pharmaceutiquement acceptables.The present invention relates to a compound of general formula (I):

in which R is a group of formula (II) following:

-CΞC-Ph-L1-(CH2)n-L2 (II)

with

• L1 representing Ph or -CΞC- or CH2,
• L2 representing H or Ph or alkylphenyl,
• n between 4 and 12,

or one of its pharmaceutically acceptable salts.

• le groupe R dans lequel L1=CH₂, n=7 et L2 =H, ce qui correspond à la structure suivante :
  
• le groupe R dans lequel L1= Ph, n=8 et L2 =H, ce qui correspond à la structure suivante :
  
• le groupe R dans lequel L1= -CΞC-, n=8 et L2= Ph, ce qui correspond à la structure suivante :
  

et l'un de ses sels pharmaceutiquement acceptables.According to a preferred embodiment, the present invention relates to a compound of general formula (I) in which the R group is chosen from:

• the group R in which L1=CH ₂ , n=7 and L2 =H, which corresponds to the following structure:
  
• the group R in which L1=Ph, n=8 and L2=H, which corresponds to the following structure:
  
• the group R in which L1= -CΞC-, n=8 and L2= Ph, which corresponds to the following structure:
  

and one of its pharmaceutically acceptable salts.

The inventors have developed new ligand-metal complexes (complexes also called chelates) from the pyclene macrocycle (3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene ), variously substituted by acetate and/or picolinate groups (methylene-6-pyridine-2-carboxylic acid). The pyclene macrocycle has the following formula:

Like the complexes described in WO 2017/109217 , the complexes according to the invention have good thermodynamic stability as well as good kinetic inertia. They can also be solubilized in an iodized oil such as ^Lipiodol® , an iodized oil manufactured and marketed by the company Guerbet and which is made up of ethyl esters of iodized fatty acids from popsicle oil. Thus, the complexes according to the invention solubilized in an iodized oil such as Lipiodol ^® can be vectored in particular towards the liver and can make it possible to visualize and/or treat cancers, for example liver cancers.

These complexes also have a good extraction yield in an iodized oil such as Lipiodol ^® . In particular, they present good incorporation of radioactivity (radiochemical yield) in an iodized oil such as Lipiodol ^® and good stability of the radioactive solution of Lipiodol ^® during in vitro tests.

In particular, the combination of the vectorization properties of Lipiodol ^® , the therapeutic effectiveness of radioelements, and the good tolerance of these products make it possible to offer a therapeutic treatment of cancers that is safe and easier to implement.

The vectorization of the complexes according to the invention with an iodized oil such as Lipiodol ^® makes it possible in particular to avoid poor delivery of the complexes and thus reduces the risk of adverse effects in healthy organs, in particular the healthy liver or in the organs. extra-hepatic, and makes it possible to achieve the effective dose of radioactivity in the tumor.

More particularly, this vectorization facilitates the work of the interventional radiologist at the time of injection of the complexes according to the invention. For example, during an intra-arterial injection followed under fluoroscopy, the radiologist's gesture will be more precise and safer by allowing an adjustment of the speed of delivery of the complexes according to the capture by the tumor of the complexes according to the invention .

Definitions

By “ligand” is meant a compound capable of complexing a chemical element such as a metal, preferably a radioelement. According to one embodiment, the ligands within the meaning of the invention are in anionic form and can complex radioelements in cationic form, for example metal cations at the oxidation state (III). According to the present invention, the compounds of formula (I) are ligands.

The term “radioelement” means any known radioisotope of a chemical element, whether natural or artificially produced. According to one embodiment, the radioelement is chosen from the radioisotopes of yttrium, actinium, copper, gallium, indium, scandium and lanthanides. By “lanthanides” are designated the atoms chosen from the group consisting of: La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb and Lu.

The term “alkylphenyl” means a linear or branched alkyl radical, preferably comprising from 1 to 20 carbon atoms, preferably from 1 to 8 carbon atoms, linked to a phenyl. Preferably, the alkylphenyl is an octylphenyl radical.

By “complex” is meant the association of a ligand as defined above with a chemical element, preferably a radioelement as defined above. The term “complex” being synonymous with “chelate”.

“Thermodynamic stability” represents the affinity of the ligand for a given element, particularly a given metal. This is the equilibrium constant of the following reaction

Metal + Ligand ⇄ Complex

whose mathematical expressions are as follows:

Dissociation constant $$\mathit{Kd}=\frac{\left[\mathit{Metal}\right]\times \left[\mathit{Ligand}\right]}{\left[\mathit{Complex}\right]}$$

Association constant $$\mathit{Ka}=\frac{\left[\mathit{Complex}\right]}{\left[\mathit{Metal}\right]\times \left[\mathit{Ligand}\right]}$$

Values are generally expressed as decimal logarithm logka or -log of Kd. According to one embodiment, the complexes according to the invention have high affinity. According to one embodiment, the complexes according to the invention have an equilibrium thermodynamic constant at least equal to 16 (LogKa at least equal to 16).

The complexes formed according to the equilibrium reaction described above are likely to dissociate under the action of different factors (pH, presence of metals or competing ligands). This dissociation can have important consequences in the context of the use of complexes in human medicine because it leads to a release of the metal in the body. In order to limit this risk, complexes with slow dissociation are sought, that is to say complexes having good kinetic inertia. Kinetic inertia can be determined by dissociation tests in an acidic medium. These experiments lead to the determination for each complex of a half-life time (T _1/2 ) under defined conditions.

In the context of the invention, the term "treat", "treatment" or "therapeutic treatment" means reversing, relieving, inhibiting the progression of, the disorder or condition to which this term is applicable, or one or more symptoms of 'such trouble.

The term “medical imaging” designates the means of acquiring and restoring images of the human or animal body from different physical phenomena such as the absorption or emission of photons (visible, infrared, X-rays, gamma rays ) nuclear magnetic resonance, reflection of ultrasound waves or radioactivity. According to one embodiment, the term “medical imaging” refers to X-ray imaging, MRI (Magnetic Resonance Imaging), single photon emission tomography (SPECT or “Single Photon Emission Computed Tomography”). ), positron emission tomoscin-tigraphy (PET) and luminescence. Preferably, the medical imaging method is X-ray imaging. SPECT if the complex according to the invention comprises a gamma emitter and PET if the complex according to the invention comprises a beta+ emitter.

The term “Lipiodol ^® ” refers to an iodized oil and preferably to the pharmaceutical specialty Lipiodol ^® , an injectable solution manufactured and marketed by Guerbet and consisting of ethyl esters of the iodized fatty acids of popsicle oil. Lipiodol ^® is a product used in particular for visualization, localization and/or vectorization during transarterial chemoembolization of hepa-tocellular carcinoma at the intermediate stage, in adults as well as for the diagnosis by selective hepatic arterial route of the hepatic extension of malignant hepatic lesions or not.

By organic acid (or organic acid function), we mean an organic compound (or an organic function) having acidic properties, that is to say capable of releasing an H ⁺ cation, or H ₃ O ⁺ in aqueous media. Among the organic acids, we can cite carboxylic acids, sulfonic acids, phosphates and phosphonates. Preferably, the organic acid functions according to the invention are carboxyl groups. Such acid functions are salifiable and can be presented in their form basic. In particular, these acid functions are in the form of pharmaceutically acceptable salts, as defined below; for example, in the form of sodium salt or meglumine (1-Deoxy-1-(methylamino)-D-glucitol or N -Methyl-D-glucamine).

Iodized oils

• Ci-Cp pour désigner une fourchette d'acides gras en Ci à Cp,
• Ci+Cp, le total des acides gras en Ci et des acides gras en Cp,

The term “fatty acid” is understood to designate saturated or unsaturated aliphatic carboxylic acids having a carbon chain of at least 4 carbon atoms. Natural fatty acids have a carbon chain of 4 to 28 carbon atoms (usually an even number). We speak of “long chain fatty acid” for a length of 14 to 22 carbons and very long chain if there are more than 22 carbons. On the contrary, we speak of “short-chain fatty acid” for a length of 4 to 10 carbons, in particular 6 to 10 carbon atoms, in particular 8 or 10 carbon atoms. Those skilled in the art know the associated nomenclature and in particular use:

• Ci-Cp to designate a range of fatty acids in Ci to Cp,
• Ci+Cp, the total fatty acids in Ci and fatty acids in Cp,

• les acides gras de 14 à 18 atomes de carbone s'écrivent « acides gras en C14-C18 »,
• le total des acides gras en C16 et des acides gras en C18 s'écrit C16 +C18,
• pour un acide gras saturé, un homme du métier utilisera la nomenclature suivante Ci : 0, où i est le nombre d'atomes de carbone de l'acide gras. L'acide palmitique sera par exemple désigné par la nomenclature (C16 :0),
• pour un acide gras insaturé, un homme du métier utilisera la nomenclature suivante Ci : x n-N où N sera la position de la double liaison dans l'acide gras insaturé en partant du carbone opposé au groupe acide, i est le nombre d'atomes de carbone de l'acide gras, x est le nombre de double liaisons (insaturations) de cet acide gras. L'acide oléique, sera par exemple désigné par la nomenclature (C18 :1 n-9).

For example :

• fatty acids with 14 to 18 carbon atoms are written “C14-C18 fatty acids”,
• the total of C16 fatty acids and C18 fatty acids is written C16 +C18,
• for a saturated fatty acid, a person skilled in the art will use the following nomenclature Ci: 0, where i is the number of carbon atoms of the fatty acid. Palmitic acid will for example be designated by the nomenclature (C16:0),
• for an unsaturated fatty acid, a person skilled in the art will use the following nomenclature Ci: x nN where N will be the position of the double bond in the unsaturated fatty acid starting from the carbon opposite the acid group, i is the number of atoms of carbon of the fatty acid, x is the number of double bonds (unsaturations) of this fatty acid. Oleic acid, for example, will be designated by the nomenclature (C18:1 n-9).

Advantageously, the iodized oil according to the invention comprises or consists of derivatives of iodized fatty acids, preferably ethyl esters of iodized fatty acids, more preferably ethyl esters of iodized fatty acids of oil. popcorn, olive oil, rapeseed oil, peanut oil, soybean oil or walnut oil, even more preferably ethyl esters of fatty acids iodized with popsicle oil or olive oil. More preferably, the iodized oil according to the invention comprises or consists of ethyl esters of iodized fatty acids from poppy oil (also called black poppy or Papaver somniferum var. nigrum ) . Flaxseed oil, also called poppy seed oil or flaxseed oil, preferably contains more than 80% unsaturated fatty acids (in particular linoleic acid (C18:2 n-6) and oleic acid (C18:1 n-9)) including at least 70% linoleic acid and at least 10% oleic acid. Iodized oil is obtained from the complete iodization of an oil such as popsicle oil under conditions allowing a bond of one iodine atom for each double bond of unsaturated fatty acids ( Wolff et al. 2001, Medicine 80, 20-36 ) followed by trans-esterification.

The iodized oil according to the invention preferably contains 29 to 53% (m/m), more preferably 37% to 39% (m/m) of iodine.

Examples of iodized oils include Lipiodol ^® , Brassiodol ^® (from rapeseed oil ( Brassica compestis ), Yodiol ^® (from peanut oil), Oriodol ^® (from from popsicle oil but in the form of fatty acid triglycerides), Duroliopaque ^® (from olive oil).

Preferably, the iodized oil is Lipiodol ^® , an iodized oil used as a contrast medium and in certain interventional radiology procedures. This oil is a mixture of ethyl esters of iodized and non-iodized fatty acids from flaxseed oil. It consists mainly (in particular, more than 84%) of a mixture of ethyl esters of long-chain iodized fatty acids (in particular C18 fatty acids) derived from flaxseed oil, preferably in a mixture of ethyl monoiodostearate and ethyl diodostearate. Iodized oil can also be an oil based on monoiodized ethyl ester of stearic acid (C18:0) from olive oil. A product of this type, called Duroliopaque ^®, was marketed a few years ago.

The main characteristics of Lipiodol ^® are as follows: Compounds Proportions in the fatty acid mixture Ethyl palmitate (Ethyl C16:0) 4.6 to 6.7% (m/m), preferably 4.8% (m/m) Ethyl stearate (Ethyl C18:0) 0.8 to 1.9% (m/m), preferably 1.2% (m/m) Ethyl monoiodostearate 11.3 to 15.3% (m/m), preferably 13.4% (m/m) Ethyl diiodostearate 73.5 to 82.8% (m/m), preferably 78.5% (m/m) Other characteristics of Lipiodol ^® : Iodine 37% to 39% (m/m) (i.e. 480 mg/ml) Viscosity at 37°C 25 mPa.s at 20°C 50 mPa.s Density 1.268 - 1.290 g/cm ³ at 20°C, preferably 1.28

Compounds of general formula (I)

According to one embodiment, the compounds of general formula (I) are in salt form, preferably in pharmaceutically acceptable salt form.

By “pharmaceutically acceptable salt” is meant in particular salts making it possible to preserve the properties and biological effectiveness of the compounds according to the invention. Examples of pharmaceutically acceptable salts are found in Berge, et al. ((1977) J. Pharm. Sd, vol. 66, 1 ). For example, the compounds of general formula (I) are in the form of sodium salt or meglumine (1-Deoxy-1-(methylamino)-D-glucitol or N-Methyl-D-glucamine).

The invention also relates to solvates such as hydrates of compounds of formula (I).

(ce composé est celui de l'exemple 11a et a pour nomenclature 6,6'-((9-(carboxymethyl)-3,6,9-triaza-1(2,6)-pyridinacyclodecaphane-3,6-diyl)bis(methylene))bis(4-((4-octylphenyl)ethynyl)picolinic acid))

(ce composé est celui de l'exemple 11b et a pour nomenclature 6,6'-((9-(carboxymethyl)-3,6,9-triaza-1(2,6)-pyridinacyclodecaphane-3,6-diyl)bis(methylene))bis(4-((4-(10-phenyldec-1-yn-1-yl)phenyl)ethynyl)picolinic acid))

(ce composé est celui de l'exemple 11c et a pour nomenclature 6,6'-((9-(carboxymethyl)-3,6,9-triaza-1(2,6)-pyridinacyclodecaphane-3,6-diyl)bis(methylene))bis(4-((4'-octyl-[1,1'-biphenyl]-4-yl)ethynyl)picolinic acid)
et l'un de leurs sels pharmaceutiquement acceptables.According to one embodiment, the compound of formula (I) is chosen from the group consisting of the following compounds:

(this compound is that of Example 11a and has the nomenclature 6,6'-((9-(carboxymethyl)-3,6,9-triaza-1(2,6)-pyridinacyclodecaphane-3,6-diyl) bis(methylene))bis(4-((4-octylphenyl)ethynyl)picolinic acid))

(this compound is that of Example 11b and has the nomenclature 6,6'-((9-(carboxymethyl)-3,6,9-triaza-1(2,6)-pyridinacyclodecaphane-3,6-diyl) bis(methylene))bis(4-((4-(10-phenyldec-1-yn-1-yl)phenyl)ethynyl)picolinic acid))

(this compound is that of example 11c and has the nomenclature 6,6'-((9-(carboxymethyl)-3,6,9-triaza-1(2,6)-pyridinacyclodecaphane-3,6-diyl) bis(methylene))bis(4-((4'-octyl-[1,1'-biphenyl]-4-yl)ethynyl)picolinic acid)
and one of their pharmaceutically acceptable salts.

ou l'un de ses sels pharmaceutiquement acceptables.According to a particular embodiment, the compound of formula (I) is the following compound:

or one of its pharmaceutically acceptable salts.

Complexes

The invention also relates to a complex of a compound of formula (I) or one of its pharmaceutically acceptable salts, as defined above, with a chemical element M, preferably a metal.

According to one embodiment, the compounds of general formula (I) are in the form of a neutral complex with cations at oxidation states III.

According to one embodiment, the chemical element M is a metal cation chosen from the group consisting of copper (II), gallium (III), indium (III), scandium (III), yttrium (III ), samarium (III), terbium (III), holmium (III), lutetium (III), actinium (III), manganese, preferably yttrium, lutetium, terbium, indium, gallium, copper and actinium. Even more preferably, the chemical element M is a metal cation chosen from the group consisting of yttrium (III), lutetium (III), copper (II) and actinium (III).

Preferably, M is a radioelement chosen from the radioactive isotopes of yttrium, lutetium, terbium, indium, gallium, copper, actinium and manganese. According to a particular embodiment, the chemical element M is a radioelement chosen from the group consisting of ⁴⁴ Sc(III), ⁴⁷ Sc(III), ¹¹¹ In(III), ¹⁵² Tb(III), ¹⁵⁵ Tb(III) , ¹⁴⁹ Tb(III), ¹⁶¹ Tb(III), ⁶⁴ Cu(III), ⁶¹ Cu(III), ⁶⁷ Cu(II) , ⁶⁸ Ga(III), ⁹⁰ Y(III), ¹⁵³ Sm(III), ¹⁶⁶ Ho(III), ¹⁷⁷ Lu(III), ⁵² Mn and ²²⁵ Ac(III), preferably ⁹⁰ Y(III), ¹⁷⁷ Lu(III), ⁶⁷ Cu(II), ²²⁵ Ac(III), ¹¹¹ In(III) ), ¹⁵² Tb(III), ¹⁵⁵ Tb(III), ¹⁴⁹ Tb(III), ¹⁶¹ Tb(III) and ⁶⁸ Ga(III).

dans laquelle le groupement R et M sont tels que définis ci-dessus.According to one embodiment, said complex has the following general formula (III):

in which the group R and M are as defined above.

The synthesis of such complexes is illustrated in examples 12 and 13.

(ce complexe de formule (III) est formé avec le composé de l'exemple 11a)

(ce complexe de formule (III) est formé avec le composé de l'exemple 11c) et

(ce complexe de formule (III) est formé avec le composé de l'exemple 11b).According to a particular embodiment, the complex of formula (III) is chosen from the group consisting of the following complexes:

(this complex of formula (III) is formed with the compound of Example 11a)

(this complex of formula (III) is formed with the compound of Example 11c) and

(this complex of formula (III) is formed with the compound of Example 11b).

Pharmaceutical composition

The invention also relates to a pharmaceutical composition comprising a compound of formula (I) as defined above or a complex of formula (III) as defined above, and possibly one or more pharmaceutically acceptable excipient(s). The pharmaceutical composition may comprise a compound of formula (I) as defined above or a complex of formula (III) as defined above, in a pharmaceutically acceptable medium. As examples, radioprotectors or antioxidants can be cited as excipients. Radiolysis means a chemical reaction caused by ionizing radiation and which is likely to initiate or accelerate degradation mechanisms of the radiopharmaceutical. A radioprotector has the property of blocking or limiting these radiochemical degradation phenomena.

The pharmaceutical composition may comprise an oily phase, in particular an iodized oil. According to a particular embodiment, the pharmaceutical composition further comprises ethyl esters of iodized fatty acids from popsicle oil.

According to one embodiment, the pharmaceutical composition according to the invention comprises at least one pharmaceutically acceptable excipient. According to another embodiment, the pharmaceutical composition according to the invention does not comprise any excipient.

According to one embodiment, the pharmaceutical composition according to the invention consists of an iodized oil and compounds or complexes according to the invention. Typically, the pharmaceutical composition according to the invention consists of Lipiodol ^® and compounds or complexes according to the invention. Lipiodol ^® is made up of ethyl esters of iodized fatty acids from popsicle oil. Preferably, the pharmaceutical composition according to the invention consists of Lipiodol ^® and the compound of Example 11b, or of Lipiodol ^® and the complex of Example 13a (ie yttrium 90 complex of the compound of Example 11b) or 13c (ie lutetium 177 complex of the compound of Example 11b).

Preferably, the pharmaceutical composition according to the invention is radiopaque, and therefore visible by X-ray radiography.

According to a particular embodiment, the pharmaceutical composition is an injectable composition. According to one embodiment, the pharmaceutical composition according to the invention is administered by intra-arterial hepatic injection.

The invention relates to a complex or a pharmaceutical composition as defined above, for its use in the treatment of cancers, in particular liver cancers.

The invention also relates to a complex or a pharmaceutical composition as defined above, for its use in medical imaging.

The invention relates to the use of a complex as defined above for the preparation of a medicament for the treatment of cancers.

The invention also relates to the use of a complex or a pharmaceutical composition as defined above in medical imaging.

The invention relates to a method of therapeutic treatment of a patient suffering from cancer, comprising administering to said patient a complex or a pharmaceutical composition as defined above. In particular, said treatment method does not include a surgical treatment step.

• une étape d'administration à un patient atteint d'un cancer d'un complexe ou d'une composition pharmaceutique selon l'invention ; et
• une étape de détection de la tumeur par une méthode d'imagerie médicale.

The invention also relates to a method of medical imaging of a tumor comprising:

• a step of administering to a patient suffering from cancer a complex or a pharmaceutical composition according to the invention; And
• a step of detecting the tumor by a medical imaging method.

By “cancer” we mean an abnormal cell proliferation (also called a tumor) within normal tissue in the body. These cancer cells all derive from the same clone, the cancer-initiating cell which has acquired certain characteristics allowing it to divide indefinitely. During the evolution of the tumor, certain cancer cells can migrate outside their place of production and form metastases.

Among the cancers, we can in particular cite liver cancers, in particular primary liver cancers, preferably hepatocarcinomas. According to a particular embodiment, mention may be made, among cancers, of hepatocarcinoma, epithelioid hemangioendothelioma, cholangiocarcinoma, neuroendocrine tumors and metastases of other cancers such as metastases of colorectal cancer.

According to a particular embodiment, the cancer is a hepatocellular carcinoma in the intermediate stage, in adults.

Process for the preparation of compounds of general formula (I) and radiolabeling

The invention also relates to a preparation process for the compounds of general formula (I) according to the invention.

In this preparation process, the deprotection steps are known to those skilled in the art and correspond to classic hydrolysis reactions of an amide. The functionalization steps are also known to those skilled in the art and correspond to classic alkylation reactions (cf. Loic Bellouard J CHEM S Perkin 1, (23), 1999, pp. 3499-3505 ).

This preparation process is advantageously based on the reaction of a diester of oxalic acid on pyclene which makes it possible to block two nitrogen atoms of pyclene (N-6 and N-9) in order to be able to intervene selectively on the third atom (N-3) left free. After functionalization of the nitrogen in position -3, the deprotection of the oxalamide group leads to a pyclene substituted in position -3 in a controlled manner, according to the following scheme 1:

According to one embodiment, the protection step is carried out in the presence of methanol.

pour former un composé de formule générale (X) suivante :

dans laquelle E2 est un groupe protecteur alkyle en C1-C4 pouvant par exemple être choisi dans le groupe constitué de méthyl, éthyle, isopropyle et terbutyle.The invention relates to a process for preparing compounds of general formula (I) comprising a step of functionalizing a compound of general formula (IX) following:

to form a compound of general formula (X) following:

in which E2 is a C1-C4 alkyl protecting group which may for example be chosen from the group consisting of methyl, ethyl, isopropyl and terbutyl.

• une étape de déprotection du composé de formule générale (X), pour obtenir un composé de formule générale (XI) suivante :
  
• une étape de fonctionnalisation du composé de formule générale (XI) selon le schéma 2, pour obtenir un composé de formule générale (I) tel que défini ci-dessus :
  

Said preparation process further comprises:

• a step of deprotecting the compound of general formula (X), to obtain a compound of general formula (XI):
  
• a step of functionalization of the compound of general formula (XI) according to scheme 2, to obtain a compound of general formula (I) as defined above:
  

E1, E2, E3 being C1-C4 alkyl protecting groups which can for example be independently chosen from the group consisting of methyl, ethyl, isopropyl and terbutyl.

dans laquelle E2 est un groupe protecteur alkyle en C1-C4 pouvant par exemple être choisi dans le groupe constitué de méthyl, éthyle, isopropyle et terbutyle.The application also describes a compound of the following general formula (X):

in which E2 is a C1-C4 alkyl protecting group which may for example be chosen from the group consisting of methyl, ethyl, isopropyl and terbutyl.

Avec R' étant un groupement de formule suivante -L1-(CH2)n-L2, où

• L1 représente Ph ou -CΞC- ou CH2,
• L2 représente H ou Ph ou alkylphényle, et
• n compris entre 4 et 12.

According to a particular embodiment of the process for preparing the compounds of formula (I), the preparation of a substituted picolinate intermediate is carried out via a brominated derivative in position -4, which allows by a coupling reaction with an alkyne, catalyzed to palladium (so-called reaction of Sonogashira, Comprehensive Chirality, Volume 4, Pages 18-32, 2012 ), to install the chosen residue, according to diagram 3 below:

With R' being a group of the following formula -L1-(CH2)n-L2, where

• L1 represents Ph or -CΞC- or CH2,
• L2 represents H or Ph or alkylphenyl, and
• n between 4 and 12.

Preferably, R' is one of the following radicals:

The invention also relates to a method for radiolabeling compounds of general formula (I). Said radiolabeling process is preferably carried out at a pH between 5 and 9, preferably between 5 and 7, preferably 5.2 in order to allow complexation. According to a particular embodiment, said radiolabeling is carried out in the presence of acetate buffer to adjust the pH and thus allow complexation. According to one embodiment, the radiolabeling is carried out in the presence of water or alcohol such as ethanol, or mixtures thereof.

The radiolabeling is carried out at a temperature between 60°C and 100°C, preferably between 80°C and 100°C, more preferably 80°C.

The radiolabeling results are presented in Table 1 below. The radiochemical purity of the complex according to the invention after complexation with yttrium 90 is expressed as a percentage of the total radioactivity involved. The percentage of extraction of the radiolabeled complex in Lipiodol ^® represents the fraction of the total radioactivity which is extracted in the oil phase. <b>Table 1</b> Ligand 90Y Complex RCP% Lipiodol ^® Extraction% Example 11a Example 15 99.7 92.9 Example 11c Example 14 92.7 89.5 Example 11b Example 13a 98.1 90.0 Ligand 1.10 ^-3 M
RCP: radiochemical purity

These data demonstrate the effectiveness of the radiolabeling of the ligands according to the invention and that the radiolabeled complexes according to the invention have a high affinity for the oily phase.

At the end of the radio-labeling operations, the radio-labeled complexes incorporated into the oily phase are engaged in a stability test in human serum. For this, the oily solutions are incubated at 37°C with moderate stirring in the presence of human serum.

The distribution of radioactivity in the oil phase and in the serum is measured at regular intervals in order to determine the fraction of radioactivity which diffuses towards the serum as a function of time. Extraction curves are thus established and make it possible to evaluate the behavior of different products and compare them. These tests are described in Example 16.

Description of figures

• Figure 1 : Release of yttrium 90 or indium 111 for the compounds of examples 13a and 13b respectively in the aqueous phase (physiological serum).
• Figure 2 : Release of yttrium 90 in human serum (aqueous phase) for the compounds of Examples 13a, 14 and 15.
• Figure 3 : Release of yttrium 90 in human serum (aqueous phase) for comparator compound 2.
• Figure 4 : Release of yttrium 90 in human serum (aqueous phase) for the compounds according to the invention of Examples 13a, 14 and 15; and for comparator compounds 3 to 5.
• Figure 5 : Evaluation of the ratio of the dose captured by the tumor relative to the healthy liver for the compound of Example 13a.
• Figure 6 : Results of biodistribution of the compound of Example 13a compared to the compound of Example 13b, Percentage of dose injected per organ.
• Figure 7 : Release of lutetium 177 in human serum and in physiological serum for the compound according to the invention of Example 13c.

The following examples are described by way of illustration of the present invention.

EXAMPLES Materials and methods Radiolabeling of ligands, synthesis of hot complexes :

Yttrium-90 chloride is purchased from PerkinElmer Life Sciences, indium-111 from Curium. Lutetium-177 nec (no carrier added) is supplied by ITM. The radioactivities involved in these examples are between 28 pCi and 8.51 mCi for yttrium (1.04 - 314.87 MBq) and 4.71 mCi (174 MBq) for indium, 673 MBq for lutetium.

The products (HPLC solvents, buffers, etc.) are used as is, without additional purification. Unless otherwise specified, the ligand is solubilized in ethanol.

The experiments were carried out in crimped borosilicate glass vials. The vials were heated in a Bioblock heating block allowing up to 6 vials to be heated. When agitation was required, a Lab Dancer S40 Vortex (VWR) was used. Centrifugations were carried out with an MF 20-R centrifuge (Awel).

Radioactivities were measured in a CRC-127R activity meter (Capintec), the calibration of which was carried out every morning.

Quality controls were carried out by thin layer chromatography (TLC) on Whatman 1 paper, with a 0.1% MeOH/NEt ₃ mixture as eluent. The Purities Radiochemicals are determined using a Cyclone phosphoimager (Perkin Elmer), using Optiquant software.

The high-performance liquid chromatography (HPLC) analyzes described according to method 10 are carried out on a Dionex Ultimate 3000 HPLC chain equipped with a diode array detector and a fLumo radiochromatographic detector (Berthold), controlled by the Chromeleon software.

In the synthesis methods described below, the commercial products as well as the solvents mainly come from the companies Sigma-Aldrich ^® , Merck and VWR ^® . The ambient temperature is between 20°C and 25°C. The solvents are evaporated under reduced pressure, using a Buchi R-210 evaporator, at temperatures of approximately 40°C.

• CombiFlash NextGen 300+ de Teledyne ISCO^® équipé d'un détecteur UV de 200 à 400nm ou UV-visible de 200 à 800nm
• Reveleris X2 de Buchi équipé d'un détecteur UV ou UV-Vis (200 à 850nm) et d'un détecteur évaporatif à diffusion de lumière (DEDL).

Purifications by flash chromatography are carried out using irregular silica gel or neutral aluminum oxide cartridges from the Buchi brand (40g, 80g, 120g, 220g or 440g) with the following devices:

• CombiFlash NextGen 300+ from Teledyne ISCO ^® equipped with a UV detector from 200 to 400nm or UV-visible from 200 to 800nm
• Reveleris X2 from Buchi equipped with a UV or UV-Vis detector (200 to 850nm) and an evaporative light scattering detector (EDLD).

The purifications on preparative HPLC columns are carried out on the PuriFlash F4250 from Interchim ^® equipped with a UV detector from 200 to 600nm and a DEDL according to method 11.

The analyzes and reaction monitoring are carried out by TLC in a tank saturated with the vapors of the eluting solvent. The support used is silica gel on a 60Â grain size glass plate with F254 fluorescent indicator or basic aluminum oxide on a glass plate or neutral on a 60Â grain size aluminum plate with F254 fluorescent indicator of the brand ^Merck® . We define the frontal ratio (Rf) of the compounds by the following calculation: $$\mathit{Rƒ}=\frac{\mathit{Distance}\mathit{line}\mathit{of}\mathit{deposit}-\mathit{compound}}{\mathit{Distance}\mathit{line}\mathit{of}\mathit{deposit}-\mathit{forehead}\mathit{of}\mathit{solvent}}$$

Analyzes and reaction monitoring are also carried out by high-performance liquid chromatography on an Agilent 1200 series chain equipped with a UV or UV/Vis G1315D DAD SL detector and processed with the EMPOWER ^® software or on a chain Shimadzu LCMS-2020 equipped with a UV or UV/Vis detector SPD-M30A and a quadrupole mass spectrometer then processed with Labsolution software. The sample introduced from the liquid chromatograph is then sprayed and ionized under atmospheric pressure by the electrospray (ESI) in positive (ES+) or negative (ES-) form. Infusions are also carried out on HPLC Ultimate 3000 RS from ThermoFisher ^® with injections of 5 µL/min and mass detection by amaZon X ion trap from Bruker ^® . The results are expressed as the mass/charge ratio (m/z).

Analysis and reaction monitoring methods

Different analysis and reaction monitoring methods were used for each of the compounds. They are described below and will be specified for each synthesis.

Method 1 : HPLC (High Performance Liquid Chromatography)

Instrument: Agilent HP1200; Column: Waters: Xbride Amide 3.5 µm; 4.6x150mm; eluent A: Acetonitrile, eluent B: 10mM formate buffer pH=3.3; flow rate 1.0mUmin; Temperature: 25°C; injection: 10µL; Wavelength 254nm; gradient: Time (minutes) %HAS %B 0 95 5 15 60 40 18 95 5 20 95 5

Method 2 : LCMS (High Performance Liquid Chromatography/Mass)

Instrument: LC/MS Shimadzu; Column: Waters: Kinextex C8 100x2.1 mm 1.7 µm; eluent A: water/trifluoroacetic acid (TFA) 0.05%, eluent B: Acetonitrile; flow rate 0.5mL/min; Temperature: 30°C; injection: 1µL; Wavelength 210nm; gradient: Time (minutes) %HAS %B 0.01 50 50 5.00 5 95 10.00 5 95 10.01 50 50 15.00 50 50

Method 3 : LCMS

Instrument: LC/MS Shimadzu; Column: ThermoFisher: Hypersil Gold 50 × 2.1mm 1.9µm; eluent A: water/formic acid 0.1% (v/v), eluent B: Acetonitrile; flow rate 0.5mL/min; Temperature: 60°C; injection: 1µL; Wavelength 260nm; gradient: Time in min % solution A % solution B Flow rate (ml/min) 0 75 25 0.5 1 75 25 0.5 11 0 100 0.5 13 0 100 0.5 14 75 25 0.5 20 75 25 0.5

Method 4: LCMS

Instrument: LC/MS Shimadzu; Column: ThermoFisher: Symmetry C18 150 × 4.6mm 5µm; eluent A: water/trifluroacetic acid 0.05% (v/v), eluent B: Acetonitrile; flow rate 1mL/min; Temperature: 25°C; injection: 1µL; Wavelength 260nm; gradient: Time in min % solution A % solution B Flow rate (ml/min) 0 98 2 1 12 0 100 1 20 0 100 1 25 98 2 1 30 98 2 1

Method 5: LCMS

Instrument: LC/MS Shimadzu; Column: Waters: Kinextex C8 100x2.1 mm 1.7 µm; eluent A: water/formic acid 0.3% (v/v); eluent B: Acetonitrile; flow rate 0.5mL/min; Temperature: 30°C; injection: 1µL; Wavelength 274nm; gradient: Time (minutes) %HAS %B 0.01 80 20 0.5 80 20 5 50 50 5.5 50 50 6.0 80 20 8.0 80 20

Method 6: LCMS

Instrument: LC/MS Shimadzu; Column: Kinextex C8 100x2.1 mm 1.7 µm; eluent A: water/formic acid 0.3% (v/v), eluent B: Acetonitrile; flow rate 0.5mL/min; Temperature: 30°C; injection: 1µL; Wavelength 274nm; gradient: Time (minutes) %HAS %B 0.01 40 60 0.5 40 60 8.0 25 75 10.0 10 90 10.5 10 90 11,000 40 60 13.00 40 60

Method 7: LCMS

Instrument: LC/MS Shimadzu; Column: Accucore C30 150×2.1mm 2.6µm; eluent A: water/formic acid 0.3% (v/v), eluent B: Acetonitrile; flow rate 0.6mL/min; Temperature: 40°C; injection: 1µL; Wavelength 320nm; gradient: Time in minutes % HAS %B 0.01 50 50 5.00 5 95 10.00 5 95 10.01 50 50 15.00 50 50

Method 8: LCMS

Instrument: LC/MS Shimadzu; Column: Hypersil GOLD Thermo Scientific 150x3m 3µm; eluent A: water/formic acid 0.1% (v/v); eluent B: Acetonitrile/formic acid 0.1% (v/v); flow rate 1mL/min; Temperature: 60°C; injection: 1µL; Wavelength 320nm; gradient: Time in minutes % HAS %B 0.01 50 50 11.00 0 100 13.00 0 100 16.00 50 50 20.00 50 50

Method 9: LCMS

Instrument: LC/MS Ultimate 3000 RS/amaZon Column: Waters, Symmetry C18 50*2.1 mm 3.5 µm; eluent A: water/trifluroacetic acid 0.05% (v/v); eluent B: Acetonitrile; flow rate 0.208mL/min; Temperature: 60°C; injection: 1µL; gradient: Time in minutes % HAS %B 0.01 98 2 4.00 0 100 6.70 0 100 14.00 98 2 20.70 98 2

Method 10 : HPLC

Instrument: Dionex Ultimate 3000 HPLC; Column: ThermoFisher, Accucore C18 100 × 3 mm, 2.6 µm; eluent A: water; eluent B: Acetonitrile; flow rate 0.4mL/min; Temperature: 25°C; gradient: Time in minutes % HAS %B 0 100 0 3.00 100 0 20.00 10 90 25.00 10 90 26.00 100 0 30.00 100 0

Method 11 : HPLC Prep (preparative column purification)

Instrument: PuriFlash F4250; Column: Waters, Symmetry C18 150*30mm 5 µm; eluent A: water/trifluroacetic acid 0.05% (v/v); eluent B: Acetonitrile; flow rate 40mL/min; Ambient temperature ; injection: 2mL

EXAMPLE 1 : synthesis of the monoalkylated macrocycle methyl 2-(3,6,9-triaza-1(2,6)-pyridinacyclodecaphane-3-yl)acetate Example 1a: Synthesis of 5-aza-1(1,4)-piperazina-3(2,6)-pyridinacycloheptaphane-12,13-dione

• Obtention d'un solide blanc m=12,7g
• Rendement = quantitatif
• Support : Oxide d'aluminium basique
• Eluant : dichlorométhane/méthanol (9 :1)
• Rf = 0,66
• Méthode HPLC : 1
• Tr (temps de rétention) = 9,0 min

The base pyclen ( Inorganic Chemistry, Volume: 36, Issue: 14, Pages: 2992-3000 ; 10g, 0.047mol) is dissolved in 400mL of methanol then added with stirring a solution of diethyloxalate (Sigma Aldrich, 1.01 equiv) dissolved in 200mL of methanol under an inert atmosphere for 20 min. Stirring of the mixture continues at room temperature for 3 hours. The solvent is then evaporated under vacuum.

• Obtaining a white solid m=12.7g
• Yield = quantitative
• Support: Basic aluminum oxide
• Eluent: dichloromethane/methanol (9:1)
• RF = 0.66
• HPLC method: 1
• Tr (retention time) = 9.0 min

Example 1b: synthesis of methyl 2-(1 ² .1 ³ -dioxo-5-aza-1(1,4)-piperazina-3(2,6)-pyridinacy-cloheptaphane-5-yl)acetate

The intermediate obtained in Example 1a (10.3g, 0.040 mol) is suspended in 260mL of acetonitrile and 1.55 equivalents of K ₂ CO ₃ are added to the suspension. The mixture thus formed is stirred under an inert atmosphere for 15 minutes. 1.01 equiv of methyl bromoacetate (Aldrich; reference: 147910-100G) dissolved in 260 mL of acetonitrile are added dropwise under an inert atmosphere for 30 minutes and left stirring for 3 hours. The solvent is then evaporated under vacuum to obtain an oil.

The crude oil is dissolved in 970ml of ethyl acetate and the salts are extracted with 35ml of water. The organic phase is dried over Na ₂ SO ₄ , filtered, then the solvent is evaporated.

• Rendement = quantitatif
• Support : Oxide d'aluminium basique
• Eluant : dichlorométhane/méthanol (9 :1)
• Rf = 0,85
• Méthode HPLC : méthode 1
• Tr = 2,7 min

We obtain a white solid m = 13.5g.

• Yield = quantitative
• Support: Basic aluminum oxide
• Eluent: dichloromethane/methanol (9:1)
• RF = 0.85
• HPLC method: method 1
• Tr = 2.7 min

Example 1b': synthesis of t-butyl-2-(1 ² .1 ³ -dioxo-5-aza-1(1,4)-piperazina-3(2,6)-pyridinacy-cloheptaphane-5-yl)acetate

The synthesis is carried out according to the procedure described in Example 1b using t-butyl bromace-tate (124230-10G, Aldrich) instead of methyl bromoacetate in the process described in Example 1b.

• m = 710 mg.
• Rendement = 99%.

We thus obtain a yellow oil.

• m = 710 mg.
• Yield = 99%.

Example 1c: synthesis of methyl 2-(3,6,9-triaza-1(2,6)-pyridinacyclodecaphane-3-yl)acetate

A solution of 13.3 g of the intermediate described in Example 1b and 11 mL of 98% sulfuric acid diluted in 265 mL of methanol are heated at reflux for 18 hours. The solution is then cooled to room temperature before adding 138 ml of Amberlyst ^® A21 resin (Aldrich; reference 216410-1KG) then left stirring for 30 minutes. The solution is filtered and the resin is rinsed with methanol.

The oil is washed three times with 50 ml of ethyl ether to remove the dimethyloxalate.

The oil is dissolved in dichloromethane, dried over MgSO ₄ , then filtered and the solvent is evaporated.

• Obtention d'un solide blanc m=4,81g
• Rendement = 43%
• Support : Oxide d'aluminium neutre
• Eluant : dichlorométhane/méthanol (9 :1)
• Rf = 0,46
• Méthode HPLC : 1
• Tr = 6,6min

The crude product is purified on flash chromatography using a 440g neutral aluminum oxide cartridge with a dichloromethane/methanol gradient.

• Obtaining a white solid m=4.81g
• Yield = 43%
• Support: Neutral aluminum oxide
• Eluent: dichloromethane/methanol (9:1)
• RF = 0.46
• HPLC method: 1
• Tr = 6.6min

The following Examples 2, 3 and 4 present the synthesis of alkynes.

EXAMPLE 2 : synthesis of 1-ethynyl-4-(10-phenyldec-1-yn-1-yl)benzene Example 2a: synthesis of dec-9-yn-1-ylbenzene

Lithium acetylenediamine complex (Aldrich, reference 186155, 1444mg 2 equiv.) is diluted in 66mL of a pentane/DMSO [7:3] mixture. The solution is stirred and degassed twice with nitrogen then cooled to 0°C. 1-bromo-8-phenyloctane (Interchim, purity 95%; reference OR8184; 2000 mg; 7.06 mmol) in solution in 7 mL of the DMSO/Et ₂ O [1:1] mixture is added then the reaction medium is stirred vigorously at room temperature for 22 hours. The solution is cooled to 0°C then 160mL of saturated NH ₄ Cl solution is added carefully. The product is extracted with 2x160mL of diethyl ether, dried over sodium sulfate (Na ₂ SO ₄ ), filtered and concentrated to dryness. The crude yellow oil is purified by flash chromatography with a silica cartridge (40g, Buchi; reference 14000024) with a heptane/dichloromethane gradient.

Obtaining a colorless liquid

• Yield = 90%
• Support: Silica
• Eluent: Heptane
• RF = 0.34
• LCMS method: 2
• Tr = 3.9min
• ¹ H NMR (300 MHz, CDCl ₃ ): δ 7.29 (m, 2H, phenyl), 7.19 (m, 3H, phenyl), 2.62 (t, J = 7.5Hz, 2H, R-CH ₂ -phenyl), 2.20 (td, J = 6.9Hz & J = 2.6Hz, 2H, R-CH ₂ -alkyne), 1.95(t, J = 2.7Hz 1H, -C=CH), 1.67-1.35 (m, 12H, lipophilic chain) .

Example 2b: synthesis of trimethyl((4-(10-phenyldec-1-yn-1-yl)phenyl)ethynyl)silane

• On obtient un liquide incolore de masse m = 1418mg
• Rendement = 93%
• Support : Silice
• Eluant : Heptane/Dichlorométhane (80 :20)
• Rf = 0,27
• Méthode LCMS : 2
• Tr = 5,9min
• ¹H RMN (60 MHz, CDCl₃) : δ 7.31 & 7.18 (m, 9H, phényl), 2.62 & 2.26 (m, 4H, R-CH₂-phényl & R-CH₂-alcyne), 1,33 (m, 12H, 6CH₂ chaine alkyle), 0,22 (s, 9H, 3xCH₃ du TMS).

The ((4-bromophenyl)ethynyl)trimethylsilane (2000mg, 7.90mmol; Aldrich, reference 494011) is diluted in 19mL of diisopropylamine, then 1,1'-Bis(diphenyl-phosphino)ferrocene (0.02 equivalent; Aldrich) is added. , reference 697230), copper iodide (0.06 equivalent; Aldrich, reference 03140) and triphenylphosphine (0.04 equivalent; Aldrich, reference T84409). The solution is degassed under an inert atmosphere and then heated to 90°C. The alkyne obtained in Example 2a (1.1 equivalent) is added through a septum then the reaction medium is stirred hot for 19 hours. The solution is cooled to room temperature, filtered through sandpaper and the residues are rinsed with diethyl ether. The filtrate is concentrated to dryness under reduced pressure. The residue is taken up with diethyl ether, washed with a saturated NaCl solution, dried over MgSOa, filtered and concentrated to dryness. The black liquid is adsorbed on silica gel 60A (Merck; reference: 1.09385.2500) and purified on a silica cartridge (40g; Buchi, reference 14000024) eluting with a heptane/dichloromethane mixture.

• A colorless liquid of mass m = 1418 mg is obtained.
• Yield = 93%
• Support: Silica
• Eluent: Heptane/Dichloromethane (80:20)
• RF = 0.27
• LCMS method: 2
• Rp = 5.9min
• ¹ H NMR (60 MHz, CDCl ₃ ): δ 7.31 & 7.18 (m, 9H, phenyl), 2.62 & 2.26 (m, 4H, R-CH ₂ -phenyl & R-CH ₂ -alkyne), 1.33 ( m, 12H, 6CH ₂ alkyl chain), 0.22 (s, 9H, 3xCH ₃ of TMS).

Example 2c: 1-ethynyl-4-(10-phenyldec-1-yn-1-yl)benzene

• On obtient un liquide incolore de masse m = 773mg
• Rendement = 67%
• Support : Silice
• Eluant : Heptane/Dichlorométhane (80 :20)
• Rf = 0,43
• Méthode LCMS : 2
• Tr = 4,9min
• ¹H NMR (60 MHz, CDCl₃) : δ 7.47-7.18 (m, 9H, phényl), 3,08 (s, 1H, CH alcyne), 2.70-2.27 (m, 4H, R-CH₂-phényl & R-CH₂-alcyne), 1,33 (m, 12H, 6xCH₂ chaine alkyle).

The intermediate obtained in Example 2b (1418 mg, 3.67 mmol) is diluted with 2.2 mL of anhydrous tetrahydrofuran. The solution is cooled in a water/ice bath then 4.4mL (1.2 equiv) of 1M tetrabutylammonium fluoride in THF (Aldrich, reference 216143) is added dropwise through a septum with a syringe and needle. The reaction medium is stirred for 2 hours at room temperature. Then 12mL of water are added before carrying out 3 extractions with 20mL of diethyl ether in order to extract the product. The organic phases are combined, and dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The yellow liquid thus obtained is purified on a silica cartridge (40g, Buchi, reference 14000024) eluting with heptane.

• A colorless liquid of mass m = 773 mg is obtained.
• Yield = 67%
• Support: Silica
• Eluent: Heptane/Dichloromethane (80:20)
• RF = 0.43
• LCMS method: 2
• Rp = 4.9min
• ¹ H NMR (60 MHz, CDCl ₃ ): δ 7.47-7.18 (m, 9H, phenyl), 3.08 (s, 1H, CH alkyne), 2.70-2.27 (m, 4H, R-CH ₂ -phenyl & R-CH ₂ -alkyne), 1.33 (m, 12H, 6xCH ₂ alkyl chain).

EXAMPLE 3 : synthesis of 1-ethynyl-4-octylbenzene Example 3a: synthesis of trimethyl((4-octylphenyl)ethynyl)silane

1-bromo-4-n-octylbenzene (3000mg, 11.14mmol, 1 equiv.; Alfa Aesar, reference A14676.06) is diluted in 27mL of diisopropylamine, then 0.02 equivalent of 1,1'-Bis(diphenylphosphino) is added. ferrocene (Aldrich, reference 697230), 0.06 equivalent of copper iodide (Aldrich, reference 03140) and 0.04 equivalent of triphenylphosphine (Aldrich, reference T84409). The solution is degassed under an inert atmosphere and then heated to 85°C before adding trimethylsilylethyne (1.1 equiv; Aldrich, reference 218170) through a septum. The reaction medium is heated for 19 hours then cooled to room temperature, filtered through sandpaper and the salts are rinsed with diethyl ether. The filtrate is concentrated to dryness under reduced pressure. The residue is taken up with diethyl ether then washed with a saturated NaCl solution. The organic phase is then dried over MgSO ₄ , filtered and the solvent is evaporated. A black liquid is obtained which will be adsorbed on silica gel 60 (Merck, reference 1.09385.2500) and purified on an 80g silica cartridge with a gradient of heptane/dichloromethane eluent.
We obtain a yellow liquid m = 2371mg
Yield = 74%
Support: Silica
Eluent: Heptane
RF = 0.43
LCMS method: method 3
Rp = 9.9min
IR: Connection Binding type Type of binding specific Peak absorption cm ^-1 Appearance ν CC C≡C Disubstituted Alkyne 2157cm ^-1 Low peak

Example 3b: synthesis of 1-ethynyl-4-octylbenzene

• On obtient un liquide incolore m = 1162mg
• Rendement = 68%
• Support : Silice
• Eluant : Heptane
• Rf = 0,42
• Méthode LCMS : 3
• Tr = 8,2min

The intermediate obtained in Example 3a (2254 mg, 7.87 mmol) is diluted in 11.8 mL of anhydrous THF then the medium is conditioned with nitrogen. The solution is cooled in a water/ice bath then 9.4mL (1.2 equivalents) of 1M tetrabutylammonium fluoride in THF (Aldrich, reference 216143) are added dropwise through a septum. The reaction medium is stirred for 2 hours at room temperature. At the end of the reaction, 40mL of water are added. The product is extracted with 80mL of diethyl ether. The organic phase is dried over Na ₂ SO ₄ , filtered and the solvent is evaporated. Obtaining a crude yellow liquid which will be purified with a silica cartridge (80g, Buchi, reference 140000025) with the eluent heptane.

• We obtain a colorless liquid m = 1162mg
• Yield = 68%
• Support: Silica
• Eluent: Heptane
• RF = 0.42
• LCMS method: 3
• Tr = 8.2min

Infrared: Connection Binding type Type of binding specific Peak absorption cm ^-1 Appearance ν CH C≡C True Alkyne 3297cm ^-1 Medium peak

EXAMPLE 4: synthesis of 4-ethynyl-4'-octyl-1,1'-biphenyl

• Obtention d'un solide blanc/jaune. M = 784mg
• Rendement =55%

Liaison Type de liaison Type de spécifique de liaison Pic d'absorption cm^-1 Apparence ν C-H C≡C Alcyne vrai 3306cm^-1 Pic moyen 1-bromo-4-n-octylbenzene (592mg, 2.2 mmol; Alfa Aesar, reference A14676.06), 4-((trimethylsilyl)ethynyl)benzeneboronic acid pinacol ester (1321mg, 2 equiv.; Interchim, H51697) and the Cs ₂ CO ₃ (3.48 eq; Alfa Aesar, reference 10924) are diluted in 10 mL of tetrahydrofuran and 4 mL of water then the solution is purged with nitrogen. Palladium II acetate (0.04 equiv., Aldrich reference: 520764), and triphenylphosphine (0.02 equiv.) are added then the reaction medium is heated to 70° C. for 20 hours away from light. The solution is cooled to room temperature, extracted with diethyl ether then the organic phase is dried over Na ₂ SO ₄ , filtered and the solvent is evaporated. The black oil is purified by flash chromatography on a silica cartridge (40g, Buchi; reference: 140000024) with the eluent heptane/AcOEt. A white/yellow solid is obtained after evaporation. The purified intermediate obtained (980 mg, 2.70 mmol) is diluted in 2.70 mL of anhydrous THF then the medium is conditioned with nitrogen. The solution is cooled in a water/ice bath then 4.59mL (1.7 eq) of 1M TBAF in THF are added dropwise through a septum. The reaction medium is stirred for 2 hours at room temperature. At the end of the reaction, 10mL of water is added. The product is extracted with 40mL of diethyl ether. The organic phase is dried over Na ₂ SO ₄ , filtered and the solvent is evaporated. Obtaining a solid which will be purified with a silica cartridge (40g, Buchi) with the eluent heptane/ethyl acetate.

• Obtaining a white/yellow solid. M = 784mg
• Yield =55%

Connection Binding type Type of binding specific Peak absorption cm ^-1 Appearance ν CH C≡C True Alkyne 3306cm ^-1 Medium peak

The following examples 5, 6, 7 and 8b illustrate the Sonogashira reaction and the synthesis of lipophilic picolinates.

EXAMPLE 5: methyl 6-(hydroxymethyl)-4-((4-(10-phenyldec-1-yn-1-yl)phenyl)ethynyl)picolinate

• Obtention d'un solide beige m =923mg
• Rendement = 53%
• CCM : Silice
• Eluant : Heptane/AcOEt (4 :6)
• Rf = 0.3
• HPLC : Méthode 4
• Tr = 16.4 min m/z (ES +) = 480,31
• RMN : ¹H NMR (60 MHz, CDCl₃) : δ 8.19 et 7.72 (m, 2H, pyridine), 7.67-7.31 (m, 9H, phenyl), 4,97 (s, 2H, CH₂OH), 4.10 (s, 3H, CH₃ ester), 3.47 (m, 1H, OH alcool primaire), 2.82-2.43 (m, 4H, R-CH₂-phényl & R-CH₂-alcyne), 1,47 (m, 12H, 6CH₂ chaine alkyle).

Methyl 4-bromo-6-(hydroxymethyl)picolinate (890mg, 3.621mmol; 1 equiv.; Interchim, reference 20210326; synthesis described in the patent WO 2017/109217 page 44) is diluted in 22mL of dimethylformamide. The solution is conditioned under an inert atmosphere then 7mL of triethylamine, Pd(PPh ₃ ) ₂ Cl ₂ (0.05 equiv.), PPh ₃ (0.1 equiv.) and Cul (0.1 equiv.) are added. ). After a few minutes of stirring, the alkyne obtained in example 2c (1-ethynyl-4-(10-phenyldec-1-yn-1-yl)benzene) (1.2 equiv.) is added to the reaction medium. and the solution is heated to 110°C. The solution cooled to room temperature then 100mL of diethyl ether are added. The organic phase is washed with 50mL of saturated NH ₄ Cl solution then with 50mL of saturated NaCl solution then it is dried with Na ₂ SO ₄ , filtered and concentrated to dryness. Obtaining a black oil which will be adsorbed on 60A silica gel and purified by flash chromatography with an 80g silica cartridge and the Heptane/AcOEt mixture.

• Obtaining a beige solid m =923mg
• Yield = 53%
• TLC: Silica
• Eluent: Heptane/AcOEt (4:6)
• RF = 0.3
• HPLC: Method 4
• Tr = 16.4 min m/z (ES +) = 480.31
• NMR: ¹ H NMR (60 MHz, CDCl ₃ ): δ 8.19 and 7.72 (m, 2H, pyridine), 7.67-7.31 (m, 9H, phenyl), 4.97 (s, 2H, CH ₂ OH), 4.10 (s, 3H, CH ₃ ester), 3.47 (m, 1H, OH primary alcohol), 2.82-2.43 (m, 4H, R-CH ₂ -phenyl & R-CH ₂ -alkyne), 1.47 (m, 12H, 6CH ₂ alkyl chain).

EXAMPLE 6 : synthesis of methyl 6-(hydroxymethyl)-4-((4-octylphenyl)ethynyl)picolinate

• Obtention d'un solide blanc m= 1852mg
• Rendement = 80%
• CCM : Silice Heptane/AcOEt (8 :2)
• Rf = 0.45
• HPLC : Méthode 4
• Tr = 15.3 min
• m/z (ES+) = 380.28

Methyl 4-bromo-6-(hydroxymethyl)picolinate (1500mg, 6.10mmol; 1 equiv.; Interchim, reference 20210326; synthesis described in the patent application WO 2017/109217 on page 44) is diluted in 37mL of anhydrous tetrahydrofuran. Then we successively carry out two degassings with nitrogen before adding 12mL of triethylamine, Pd(PPh ₃ ) ₂ Cl ₂ (0.05 equiv.), PPh ₃ (0.1 equiv.) and Cul ( 0.1 equiv.). After a few minutes of stirring, the alkyne obtained in Example 3b, (1-ethynyl-4-octylbenzene) (1.2 equiv.), is added to the reaction medium and the solution is heated to 40°C. The solution is cooled to room temperature, filtered through sandpaper (Whatman) and the residues are rinsed with 100mL of Et ₂ O. The filtrate is washed with 100mL of saturated NH ₄ Cl solution and 40mL of saturated NaCl solution then the organic phase is dried over Na ₂ SO ₄ , filtered and concentrated to dryness. A black oil is obtained which will be adsorbed on 60A silica gel and purified by flash chromatography with a silica cartridge (Buchi; 80g) and the Heptane/AcOEt mixture.

• Obtaining a white solid m=1852mg
• Yield = 80%
• TLC: Silica Heptane/AcOEt (8:2)
• RF = 0.45
• HPLC: Method 4
• Tr = 15.3 min
• m/z (ES+) = 380.28

EXAMPLE 7 : synthesis of methyl 6-(hydroxymethyl)-4-((4'-octyl-[1,1'-biphenyl]-4-yl)ethynyl)picolinate

• Obtention d'un solide beige m= 1668mg
• Rendement = 75%
• m/z (ES +) = 456

Methyl 4-bromo-6-(hydroxymethyl)picolinate (4.88mmol; 1 equiv.; Interchim, reference 20210326; synthesis described in the patent application WO 2017/109217 on page 44), anhydrous THF (6.1mUmmol) and after 2 degassings with nitrogen, the alkyne obtained in Example 4 (4-ethynyl-4'-octyl-1,1'-biphenyl) (1 .1 equiv.), Et ₃ N (2mUmmol), Pd(PPh ₃ ) ₂ Cl ₂ (0.1 equiv.) and Cul(0.1 equiv.) are mixed. The solution becomes black and the reaction medium is stirred at 40°C in an inert medium. The solution is cooled to room temperature, filtered through sandpaper (Whatman), the residues are rinsed with 100mL of Et ₂ O. The organic phase is washed twice with 100mL of saturated NH ₄ Cl solution and 1×100mL of saturated NaCl solution. It is then dried over Na ₂ SO ₄ , filtered and concentrated to dryness. Obtaining a black oil which will be adsorbed on silica and purified by flash chromatography with a silica cartridge and the Heptane/AcOEt mixture.

• Obtaining a beige solid m= 1668mg
• Yield = 75%
• m/z (ES +) = 456

The following Example 8 presents the synthesis of the compound obtained in Example 5, (methyl 6-(hydroxymethyl)-4-((4-(10-phenyldec-1-yn-1-yl)phenyl)ethynyl)picolinate) , via a reaction to protect the alcohol by acetylation.

EXAMPLE 8 : Example 8a : synthesis of methyl 6-(acetoxymethyl)-4-bromopicolinate

• On obtient un solide blanc m=33,65g.
• Rendement quantitatif
• Support : Silice gel
• Eluant : Heptane/AcOEt (4 :6)
• Rf= 0.6
• Méthode HPLC : 5Tr = 3,56min
• m/z (ES +) = 288
• RMN : ¹H NMR (60 MHz, CDCl₃) : δ 8.19 et 7.72 (m, 2H, pyridine), 5,35 (s, 2H, CH₂Ac), 4.07 (s, 3H, CH₃ ester), 2,25 (s, 3H, CH₃ acétate)

The intermediate methyl 6-(hydroxymethyl)-4-bromopicolinate (25.409g; 103.26mmol) is diluted in 516mL of dichloromethane then the medium is conditioned under a nitrogen atmosphere. 26mL of triethylamine are added at once and acetic anhydride (7.6 equiv; Aldrich, 242845) is added dropwise via a dropping funnel and then the reaction medium is stirred for 2 hours at room temperature. The organic phase is washed with 50 mL of osmosis water, dried on Na ₂ SO ₄ , filtered and concentrated to dryness.

• We obtain a white solid m=33.65g.
• Quantitative yield
• Support: Silica gel
• Eluent: Heptane/AcOEt (4:6)
• Rf= 0.6
• HPLC method: 5Tr = 3.56min
• m/z (ES +) = 288
• NMR: ¹ H NMR (60 MHz, CDCl ₃ ): δ 8.19 and 7.72 (m, 2H, pyridine), 5.35 (s, 2H, CH ₂ Ac), 4.07 (s, 3H, CH ₃ ester), 2 .25 (s, 3H, CH ₃ acetate)

Example 8b: synthesis of methyl 6-(acetoxymethyl)-4-((4-(10-phenyldec-1-yn-1-yl)phenyl)ethynyl)picolinate

The compound obtained in Example 8a (20.53g, 71.36mmol) is diluted in 800mL of tetrahydrofuran then the solution is conditioned under an inert atmosphere. Triphenylphosphine (0.1 equiv), Pd(PPh ₃ ) ₂ Cl ₂ (0.05 equiv), Cul (0.1 equiv) and 143mL Et ₃ N are added to the solution. The compound obtained in Example 2c in solution in 200 mL of tetrahydrofuran is added all at once to the reaction medium then the solution is heated to 60° C. for 50 min. The reaction medium is cooled to room temperature, filtered and rinsed with 250 mL of tetrahydrofuran. The solvent is evaporated under vacuum. The crude product is then redissolved in 910mL of diethyl ether, filtered then the organic phase is washed with 500mL of saturated NH ₄ Cl solution, 500mL of saturated Na ₂ CO ₃ solution and 250mL of saturated NaCl solution. The organic phase is dried over Na ₂ SO ₄ , filtered then concentrated under vacuum. Obtaining a brown solid which is recrystallized in a heptane/AcOEt mixture with hot filtration.

• Rendement = 96%
• Support : Silice gel
• Eluant : Heptane/AcOEt (4 :6)
• Rf = 0.65
• Méthode HPLC : Tr = 8.15min
• m/z (ES+) = 522
• RMN : ¹H NMR (60 MHz, CDCl₃) : δ 8.11 et 7.57 (m, 2H, pyridine), 7.42-7.19 (m, 9H, phenyl), 5,30 (s, 2H, CH₂Ac), 3.99 (s, 3H, CH₃ ester), 2.59-2.30 (m, 4H, R-CH₂-phényl & R-CH₂-alcyne), 2,17 (s, 3H, CH₃ acétate), 1,35 (m, 12H, 6CH₂ chaine alkyle).

The solid is then rinsed with 100mL of cold AcOEt to obtain a white solid m=35.58g

• Yield = 96%
• Support: Silica gel
• Eluent: Heptane/AcOEt (4:6)
• RF = 0.65
• HPLC method: Tr = 8.15min
• m/z (ES+) = 522
• NMR: ¹ H NMR (60 MHz, CDCl ₃ ): δ 8.11 and 7.57 (m, 2H, pyridine), 7.42-7.19 (m, 9H, phenyl), 5.30 (s, 2H, CH ₂ Ac), 3.99 (s, 3H, CH ₃ ester), 2.59-2.30 (m, 4H, R-CH ₂ -phenyl & R-CH ₂ -alkyne), 2.17 (s, 3H, CH ₃ acetate), 1.35 ( m, 12H, 6CH ₂ alkyl chain).

Example 8c: synthesis of the compound according to Example 5 (methyl 6-(hydroxymethyl)-4-((4-(10-phenyldec-1-yn-1-yl)phenyl)ethynyl)picolinate) from the intermediate obtained in example 8b

The intermediate obtained in Example 8b (33.36g, 63.95mmol) is diluted in 255mL of methanol. Addition of 27mL of triethylamine (3 equiv) then the reaction medium is heated at reflux for 23 hours. The reaction medium is filtered then the filtrate is cooled in an acetone/dry ice bath. After filtration, a white solid of mass m=22.91g is obtained.
Yield = 75%

The following Example 9 illustrates the activation reactions of alcohol in mesylate form.

EXAMPLE 9 : synthesis of substituted methyl-4-6-(((methylsulfonyl)oxy)methyl)picolinate

Structure Nomenclature Brute formula Example 9a

methyl 6-(((methyl-sulfonyl)oxy)methyl)-4-((4-octylphenyl)ethynyl)picolinate C25H31NO5S Example 9b

methyl 6-(((methyl-sulfonyl)oxy)methyl)-4-((4-(10-phenyldec-1-yn-1-yl)phenyl)ethynyl)picolinate C33H35NO5S Example 9c

methyl 6-(((methyl-sulfonyl)oxy)methyl)-4-((4'-octyl-[1,1'-biphenyl]-4-yl)ethynyl)picolinate C31H35NO5S

The intermediate obtained in Example 5, 6 or 7 (1.64mmol, 1 equiv.) is diluted in 18mL of DCM (11mUmmol). The solution is packaged under an inert atmosphere and then cooled in a water/ice bath. Triethylamine (3 equiv) and mesyl chloride (1.5 equiv) are added dropwise. The reaction medium is stirred for 10 min then 18 mL of saturated NaHCOs solution is added to end the reaction. The organic phase is recovered, dried over Na ₂ SO ₄ and concentrated to dryness. Obtaining a yellow solid which will be purified by flash chromatography on a silica cartridge with the Heptane/AcOEt mixture.

The results are presented in the following table: Example 9a Example 9b Example 9c Molar mass 457.59 557.71 533.68 Yield 97% 97% 63% LCMS method Method 8 Method 4 Method 9 Tr 8.1 mins 9.7 mins ND m/z (ES+) 458 558.31 534 a: NMR: ¹ H NMR (60 MHz, CDCl ₃ ): δ 8.20 and 7.76 (m, 2H, pyridine), 7.48-7.24 (m, 9H, phenyl), 5.45 (s, 2H, CH ₂ OH) , 4.04 (s, 3H, CH ₃ ester), 3.19 (s, 3H, CH ₃ mesyl), 2.75-2.36 (m, 4H, R-CH ₂ -phenyl & R-CH ₂ -alkyne), 1, 40 (m, 12H, 6CH ₂ alkyl chain).

The following Example 10 illustrates the alkylation reactions of the compound obtained in Example 1c with the mesylated reagents described in Example 9.

EXAMPLE 10 : Alkylation of the intermediate obtained in Example 1c (methyl 2-(3,6,9-triaza-1(2,6)-pyridinacyclodecaphane-3-yl)acetate)

Structure Name Brute formula Example 10a

dimethyl 6,6'-((9-(2-methoxy-2-oxoethyl)-3,6,9-triaza-1(2,6)-pyridina-cyclodecaphane-3,6-diyl)bis(methylene)) bis(4-((4-octylphenyl)ethynyl)picolinate) C62H76N6O6 Example 10b

dimethyl 6,6'-((9-(2-methoxy-2-oxoethyl)-3,6,9-triaza-1(2,6)-pyridina-cyclodecaphane-3,6-diyl)bis(methylene)) bis(4-((4-(10-phenyldec-1-yn-1-yl)phenyl)ethynyl)picolinate) C78H84N6O6 Example 10c

dimethyl 6,6'-((9-(2-methoxy-2-oxoethyl)-3,6,9-triaza-1(2,6)-pyridina-cyclodecaphane-3,6-diyl)bis(methylene)) bis(4-((4'-octyl-[1,1'-biphenyl]-4-yl)ethynyl)picolinate) C74H84N6O6

The compound obtained in Example 1c (methyl 2-(3,6,9-triaza-1(2,6)-pyridinacyclodecaphane-3-yl)acetate) (462mg, 1.66mmol, 1 equivalent) is diluted in 30mL of anhydrous acetonitrile then the calcined calcium carbonate (2.5 equivalents) and the intermediate obtained in Example 9 (9a or 9b or 9c) (2.1 equivalents) are added. The reaction medium is heated to 60° C. with stirring. The solution is then cooled to room temperature and filtered. The salts are rinsed with acetonitrile then the filtrate is concentrated to dryness. An orange oil is obtained which will be purified by flash chromatography with a silica cartridge with the DCM/MeOH mixture. Example 10a Example 10b Example 10c Mass 1001.33 1201.57 1153.52 Yield 45% 50% 23% Eluent TLC DCM/MeOH 8:2, Silica DCM/MeOH 9:1, Silica DCM/MeOH 8:2, Silica RF=0.78 RF=0.38 LCMS method Method 4 Method 4 Method 4 Tr 16.1 mins 14.3 mins 14.4min m/z (ES+) 1002 1202 1153.7

The following Example 11 illustrates the production of lipophilic ligands.

EXAMPLE 11: Saponification of the intermediates obtained in Example 10, to obtain the compounds of formula (I)

Composés de formule (I) selon l'invention Structure Nomenclature Formule brute Exemple 11a

6,6'-((9-(carboxymethyl)-3,6,9-triaza-1(2,6)-pyridina-cyclodecaphane-3,6-diyl)bis(methylene))bis(4-((4-octylphenyl)ethynyl)picolinic acid) C59H70N6O6 Exemple 11b

6,6'-((9-(carboxymethyl)-3,6,9-triaza-1(2,6)-pyridina-cyclodecaphane-3,6-diyl)bis(methylene))bis(4-((4-(10-phenyldec-1-yn-1-yl)phenyl)ethynyl)picolinic acid) C75H78N6O6 Exemple 11c

6,6'-((9-(carboxymethyl)-3,6,9-triaza-1(2,6)-pyridina-cyclodecaphane-3,6-diyl)bis(methylene))bis(4-((4'-octyl-[1,1'-biphenyl]-4-yl)ethynyl)picolinic acid) C71H78N6O6 The R groups are chosen from:

Compounds of formula (I) according to the invention Structure Nomenclature Brute formula Example 11a

6,6'-((9-(carboxymethyl)-3,6,9-triaza-1(2,6)-pyridina-cyclodecaphane-3,6-diyl)bis(methylene))bis(4-((4 -octylphenyl)ethynyl)picolinic acid) C59H70N6O6 Example 11b

6,6'-((9-(carboxymethyl)-3,6,9-triaza-1(2,6)-pyridina-cyclodecaphane-3,6-diyl)bis(methylene))bis(4-((4 -(10-phenyldec-1-yn-1-yl)phenyl)ethynyl)picolinic acid) C75H78N6O6 Example 11c

6,6'-((9-(carboxymethyl)-3,6,9-triaza-1(2,6)-pyridina-cyclodecaphane-3,6-diyl)bis(methylene))bis(4-((4 '-octyl-[1,1'-biphenyl]-4-yl)ethynyl)picolinic acid) C71H78N6O6

The intermediate obtained in Example 10 (10a or 10b or 10c) (1.00 mmol, 1 equivalent) is diluted in 10 mL of 2M potassium hydroxide solution in ethanol. The reaction medium is stirred at room temperature for 15 min. Addition of 15mL of DCM then the solution is cooled in a water/ice bath before adding 30% hydrochloric acid without metals until a pH 6-7 and a precipitate are obtained. The salts are filtered, rinsed with DCM then the filtrate is concentrated to dryness. A crude yellow solid is obtained which will be purified on a preparative column except for compound 11c which will be left crude.

The fractions enriched with the product of interest are combined, concentrated under vacuum then freeze-dried. Example 11a Example 11b Example 11c Molar mass 959.25 1159.49 1111.44 Yield 41% (purified) 26% (purified) 42% (gross) LCMS method Method 4 Method 4 Method 9 Tr 13.3 mins 13.93 mins 9.0 mins m/z (ES+) 959.6 1159.7 1111.6

Examples 12, 13, 14 and 15 illustrate complexation reactions with different metals of interest.

EXAMPLE 12 : syntheses of complexes of formula (III) according to the invention Example 12a: synthesis of the metal(III) complex 6,6'-((9-(carboxylatomethyl)-3,6,9-triaza-1(2,6)-pyridinacyclodecaphane-3,6-diyl)bis(methylene) )bis(4-((4-(10-phenyldec-1 -yn-1 -yl)phenyl)ethynyl)picolinate)

Complexes of formula (III) according to the invention Reagent M Nomenclature Brute formula Example 12a YCl _3.6 (H ₂ O) Y ⁸⁹ Yttrium(III) 6,6'-((9-(carboxylatomethyl)-3,6,9-triaza-1(2,6)-pyridina-cyclodecaphane-3,6-diyl)bis(methylene))bis(4 -((4-(10-phenyldec-1-yn-1-yl)phenyl)ethynyl)picolinate) C75H75N6O6Y Strem Chemicals Ref: 93-3903 Example 12b LuCl _3.6 (H ₂ O) Lutetium(III) 6,6'-((9-(carboxylatomethyl)-3,6,9-triaza-1(2,6)-pyridinacyclodecaphane-3,6-diyl)bis(methylene))bis(4-( (4-(10-phenyldec-1-yn-1-yl)phenyl)ethynyl)picolinate) C75H75LuN6O6 Strem Chemicals Ref: 93-7111 Nat. Read Example 12c TbCl _3.6 (H ₂ O) TB ¹⁵⁹ Terbium(lll) 6,6'-((9-(carboxylatomethyl)-3,6,9-triaza-1(2,6)-pyridinacyclodecaphane-3,6-diyl)bis(methylene))bis(4-( (4-(10-phenyldec-1-yn-1-yl)phenyl)ethynyl)picolinate) C75H75N6O6Tb Alfa Aesar Ref: 11210

50 mg of ligand obtained in Example 11b are dissolved in 13.3 mL of methanol and the hexahydrated metal hydrochloride (1.5 equiv) is added to the medium. The pH of the solution is adjusted to 6 using a solution of sodium methanolate (0.12M) then the reaction medium is stirred at room temperature for 30 min. The solution is concentrated to dryness then the crude solid is treated with 4 mL of dichloromethane. The solvent is then evaporated under reduced pressure to obtain a yellow solid. Example 12a Example 12b Example 12c Molar mass 1245.37 1331.43 1315.39 Yield Quantitative Quantitative Quantitative HPLC method Method 7 Infusion Infusion Tr 7.05min N / A N / A m/z (ES+) 1246.6 1331.6 1315.5

EXAMPLE 13 : synthesis of radiolabeled complexes Example 13a : synthesis of the Yttrium 90 complex of the ligand prepared in step 11b (6,6'-((9-(carboxymethyl)-3,6,9-triaza-1 (2,6)-pyridinacyclodecaphane-3 ,6-diyl)bis(methylene))bis(4-((4-(10-phenyldec-1-yn-1-yl)phenyl)ethynyl)picolinic acid))

500 µL of solution of the compound obtained in Example 11b (C = ^10-3 mol/L) are taken and placed in an SF8 glass vial, 500 µL of a buffered solution of 3M sodium acetate pH5.2 are added to a batch of approximately 629MBq (17mCi) of [90Y] chloride ([90Y]CI) (Perkin Elmer). The radioactive solution (-500 µl) is then recovered and placed in the vial containing the 500 µ! of ligand solution. The mixture is shaken slightly before being incubated at 80°C for 20 min. At the end of the reaction, a sample is taken using an insulin syringe and placed on a thin layer chromatography plate (Chromatography paper 1CHR, GE). The quantity of radioactivity in the vial is measured using an ionization chamber (VDC-405 activity meter, model VIK202, used with software v3.29; Comecer Netherlands, Netherlands) previously calibrated for measuring radioactivity. the radioactivity emitted by the disintegration of [90Y] packaged in a glass bottle and re-suspended in a water/ethanol medium.

The extraction is then carried out in Lipiodol ^® .

1 mL of physiological serum (Mini-Plasco NaCl 0.9%, BBraun), then 2 ml of Lipiodol ^® Ultra Fluide (Guerbet), are added successively to the reaction medium resulting from the radiolabeling contained in the vial and the latter is shaken vigorously manually. using tongs to emulsify. The emulsion is then broken by centrifugation (2600g, 20 min) (Sigma 2-6, Fisher Bioblock Scientific) allowing the production of a lower oily phase, consisting of Lipiodol ^® (called “Lipiodolic phase”) containing the radiolabeled complex and an upper phase containing the water/ethanol mixture. The quantity of radioactivity contained in the bottle is measured using the same ionization chamber previously calibrated for the measurement of [ ⁹⁰ Y] in ^Lipiodol® . The majority of the upper phase is aspirated by syringe. The Lipidolic phase is then collected using a 23G0, 60X25mm needle (Sterican, BBraun), attached to a 1.0ml syringe (1ml Syringe Luer BD Plastipak, BD) in a pre-weighed SF8 glass vial.

The quantity of radioactivity contained in the vials containing respectively the ethanol/ligand phase and the Lipiodolic phase is measured using the ionization chamber previously calibrated for each of the measurement conditions. The bottle containing the Lipiodolic phase is weighed using a precision balance (model TE64-0CE, Sartorius) allowing the calculation of the volume activity of the radio tracer.

Calculations of the synthesis yields of the radio tracer, its radiochemical purity and its volume activity : Synthesis yield

The synthesis yield of the targeted radio tracer was established to be greater than or equal to 50%. It was calculated according to the following formula: $$\mathrm{R}=\frac{\mathit{activity}\mathit{of}\mathit{there}\mathit{phase}\mathit{lipiodolic}r\mathrm{e}\mathrm{vs}up\mathrm{e}r\mathrm{e}e}{\mathit{activity}\mathit{engaged}\mathit{measured}\mathit{post}-\mathit{incubator}\mathrm{has}{80}^{\circ }\mathrm{VS})}\times 100\%$$

Radiochemical purity (PRC) by thin layer chromatography

The plates (Chromatography paper 1CHR, GE) are eluted with a solution of triethylamine (Et ₃ N) 0.1% by volume in methanol (MeOH) until the migration front reaches the top of the sheet. The radioactivity present on the dried leaves is then detected using a FLA-7000 phosphorimager operating with the acquisition software of the same name (version 1.1, FujiFilm). The PRC of the radio-labeled ligand was calculated using the Multi Gauge v3.1 program (FujiFilm), based on the quantification of the radioactivity detected on the sheet where the reaction medium had migrated. In practice this quantification is based on the creation of regions of interest traced on each of the zones associated with the radioactivity detected. The PRC was calculated as follows: $$\mathrm{PRC}=\frac{r\mathrm{has}dio\mathrm{has}\mathrm{vs}tivit\mathrm{e}\mathrm{has}sso\mathrm{vs}i\mathrm{e}e\mathit{At}\mathit{ligand}\left(\mathit{PSL}\right)}{r\mathrm{has}dio\mathrm{has}\mathrm{vs}tivit\mathrm{e}\mathit{corresponding}\mathrm{has}L\prime \left[90\right]\mathit{free}pr\mathrm{e}\mathit{feels}\mathit{In}\mathit{THE}\mathit{medium}r\mathrm{e}\mathit{actionable}\left(\mathit{PSL}\right)}\times 100\%$$

Calculation of activity concentration

avec $\mathrm{activité}\mathrm{massique}\left(\mathrm{MBq}/\mathrm{g}\right)=\frac{activit\mathrm{é}\left(\mathit{phase}\mathit{lipiodolique}\right)\left(\mathit{MBq}\right)}{\mathit{masse}\mathit{lipiodol}\left(g\right)}$

et $$\mathrm{masse}\mathrm{Lipiodol}\left(\mathrm{g}\right)=\mathit{masse}\left(\mathit{fiole}\mathit{pleine}\right)-\mathit{masse}\left(\mathit{fiole}\mathit{vide},pré\mathrm{-}\mathit{pesée}\right)$$

et $$\mathrm{masse}\mathrm{Lipiodol}\circledR \left(\mathrm{g}\right)=\mathrm{masse}\left(\mathrm{fiole}\mathrm{pleine}\right)\mathrm{-masse}\left(\mathrm{fiole}\mathrm{vide},\mathrm{pré-pesée}\right)$$

The volume activity is determined by weighing the bottle in which the Lipiodolic phase containing the radio tracer was recovered and by measuring the [90Y] activity using an ionization chamber (the measured activity is corrected for the cosmic background noise as well as for the physical decay of [ ⁹⁰ Y] (“background noise”). It will be calculated as follows, taking into account the value of 1.28g/mL as the density of Lipiodol ^® : $$\mathrm{activity}\mathrm{volume}\left(\mathrm{MBq}/\mathrm{ml}\right)=\mathrm{has}\mathrm{vs}tivit\mathrm{e}\mathit{mass}\left(\frac{\mathit{MBq}}{g}\right)\times de\mathrm{not}sit\mathrm{e}\left(\mathit{lipiodol}\right)\left(\frac{g}{\mathit{ml}}\right)$$

with $\mathrm{activity}\mathrm{mass}\left(\mathrm{MBq}/\mathrm{g}\right)=\frac{\mathrm{has}\mathrm{vs}tivit\mathrm{e}\left(\mathit{phase}\mathit{lipiodolic}\right)\left(\mathit{MBq}\right)}{\mathit{mass}\mathit{lipiodol}\left(g\right)}$

And $$\mathrm{mass}\mathrm{Lipiodol}\left(\mathrm{g}\right)=\mathit{mass}\left(\mathit{flask}\mathit{full}\right)-\mathit{mass}\left(\mathit{flask}\mathit{empty},pre\mathrm{-}\mathit{weighing}\right)$$

And $$\mathrm{mass}\mathrm{Lipiodol}\circledR \left(\mathrm{g}\right)=\mathrm{mass}\left(\mathrm{flask}\mathrm{full}\right)\mathrm{-mass}\left(\mathrm{flask}\mathrm{empty},\mathrm{pre-weighed}\right)$$

Example 13b : indium 111 complex of the ligand obtained in Example 11b (6,6'-((9-(carboxymethyl)-3,6,9-triaza-1(2,6)-pyridinacyclodecaphane-3,6 -diyl)bis(methylene))bis(4-((4-(10-phenyldec-1-yn-1-yl)phenyl)ethynyl)picolinic acid))

The same protocol as that described in Example 13a using a solution of indium 111 (Curium, 4.71 mCi, 174 MBq) leads to the formation of the indium 111 complex.

Example 13c : luthenium 177 complex of the ligand obtained in Example 11b (6,6'-((9-(carboxymethyl)-3,6,9-triaza-1(2,6)-pyridinacyclodecaphane-3,6- diyl)bis(methylene))bis(4-((4-(10-phenyldec-1-yn-1-yl)phenyl)ethynyl)picolinic acid))

The same protocol as that described in Example 13a using a solution of lutetium 177 (673 MBq) leads to the formation of the lutetium 177 complex.

Lipiodol ^® marking results

Example 13a Example 13b Example 13c Radio Chemical Purity (%) 99.2 95.5 94.1 Yield (%) 99 94.5 87.4

EXAMPLE 14: Yttrium 90 complex of the compound obtained in Example 11c (6,6'-((9-(carboxymethyl)-3,6,9-triaza-1(2,6)-pyridinacyclodecaphane-3,6 -diyl)bis(methylene))bis(4-((4'-octyl-[1,1'-biphenyl]-4-yl)ethynyl)picolinic acid))

0.5 mL of yttrium-90 chloride in acetate buffer solution pH = 5.2 are added to 0.5 mL of ligand obtained in Example 11c in solution in DMSO at a concentration of 10 ^-3 mol/L . The solution is heated for 15 min at 80°C. 1 mL of physiological serum + 2 mL of Lipiodol ^® are added and the mixture is shaken vigorously. The phases are then separated by centrifugation (4500 rpm, 20 min) and the oily phase is collected to obtain the expected radiotracer. PRC (%) 92.7 Yield (%) 89.5

EXAMPLE 15: Yttrium 90 complex of the compound obtained in Example 11a (6,6'-((9-(carboxymethyl)-3,6,9-triaza-1(2,6)-pyridinacyclodecaphane-3,6 -diyl)bis(methylene))bis(4-((4-octylphenyl)ethynyl)picolinic acid))

0.5 mL of yttrium-90 chloride in acetate buffer solution pH = 5.2 are added to 0.5 mL of ligand obtained in Example 11a in solution in ethanol at a concentration of 10 ^-3 mol/ L. The solution is heated for 15 min at 80°C. 1 mL of physiological serum + 2 mL of Lipiodol ^® are added and the mixture is shaken vigorously. The phases are then separated by centrifugation (3500 rpm, 15 min) and the oily phase is collected to obtain the expected radiotracer. PRC (%) 99.7 Yield (%) 92.9

EXAMPLE 16 : Stability studies 1/ With the compounds according to the invention :

The radiolabeled prototypes (labeled Lipiodol ^® ) are then engaged in stability tests, consisting of an incubation period at 37°C in the presence of serum (physiological or human) and kinetic monitoring of the passage of radioactivity from the oily phase to the aqueous phase. These results are presented in the form of release curves indicating on the x-axis the incubation time (in hours) and on the y-axis the release rate (% of the radioactivity transferred to the aqueous phase).

1 mL of freshly prepared radiotracer (examples 13a, 13b, 13c, 14, 15) is taken and then placed in a 12 mL flat-bottomed glass vial. The radioactivity is measured with the activity meter, and the time noted. 10 mL of serum (physiological or human) are added before stirring the mixture. The vial is then placed in the incubator at 37°C, with a shaker set at 30 rpm.

The agitation is left for several days. The aqueous phase is taken at different times to determine yttrium-90 (radiolabeled complex of Example 13a, Example 14 and Example 15); indium-111 (radiolabeled complex of Example 13b) or lutetium 177 (radiolabeled complex of Example 13c) released.

The results of release of yttrium 90 or indium 111 for the compounds of examples 13a and 13b respectively in the aqueous phase (physiological serum) are presented in the figure 1 .

The results of release of yttrium 90 in human serum (aqueous phase) for the compounds of Examples 13a, 14 and 15 are presented in the figure 2 .

The results of release of lutetium 177 in physiological serum and in human serum for the compound of Example 13c are presented in the Figure 7 . These results show that the lutetium 177 complex of Example 13c presents a stability in sera equivalent to that observed for the compounds of Examples 13a and 13b (yttrium 90 complexes and indium 111 complex.

THE figures 1 , 2 And 7 show that the compounds which are the subject of the invention are stable in physiological and human serum, that is to say that the radioactivity remains in the Lipiodol phase and does not leak into the aqueous phase (less than 30% release for the compounds of Examples 14 and 15 and less than approximately 10% release for the compounds of Examples 13a, 13b and 13c), over a period of at least 350 hours, which makes it possible to envisage their use in radiotherapy of liver tumors .

2/ With comparative compounds :

The following comparative compounds were studied under the same conditions in order to be able to compare their properties with the compounds of the invention.

a) Structure of comparator picolinates:

Comparator 1 Comparator 2 R H C≡CH-(CH ₂ ) ₉ CH ₃ Comparator 1 Comparator 2 Radiolabelling 1 PRC (%) 98 98 Extraction 1 yield (%) 0 89.8 Radiolabelling 2 PRC (%) - 98.9 Extraction 2 yield (%) - 14.6 Radiolabelling 3 PRC (%) - 69.7 Extraction 3 yield (%) - 17

Comparator product 1 devoid of lipophilic residue on the picolinate units is not extracted in Lipiodol ^® .

The results obtained with comparator product 2 indicate that radiolabeling and extraction in Lipiodol ^® are not reproducible for this substance.

These results contrast with those described in Example 17 with perfectly reproducible radiolabeling for the compound described in Example 11b.

In addition, the stability of comparator 2 in human serum under the experimental conditions described above is shown in Figure 3 ; it is significantly worse than that observed for the products according to the invention ( figure 2 ).

Indeed on the Figure 3 we see that more than 50% of the radioactivity has already leaked into the aqueous phase at T0 + 200 hours. Compound Comparator 2 Example 13a Example 14 Example 15 Leakage of radioactivity into the serum at 216H (%) 58 3 21 12.5

This indicates that the structure of the lipophilic residue R installed on the picolinate units is critical for obtaining equivalent properties (radiolabeling, reproducibility and stability) to the compounds of the invention.

During the optimization of lipophilic residues, structure-related prototypes were prepared and tested. It appeared that the structure of the R group had to be adjusted very finely in order to obtain stable compounds during the test carried out in physiological serum.

b) Structures comparator compounds 3, 4, 5 :

The extraction data in Lipiodol ^® for the different compounds prepared are presented in the following table: Comparator 3 Example 15 Comparator 4 Comparator 5 Example 14 Example 13a Lipiodol ^® extraction (%) 51.0 92.9 93.4 84.5 89.5 90.0

Stability data is presented on the Figure 4 .

The stability curves of the compounds of the invention show a slower transfer of radioactivity to the serum and a lower amplitude than the three comparator compounds. Indeed, none of these three comparator compounds is stable in serum, that is to say they exhibit rapid and significant leakage of radioactivity towards the aqueous phase.

This indicates that the structure of these compounds does not allow stable radiolabeled oil phases to be obtained.

EXAMPLE 17 : Biodistribution study of the compound obtained in Example 13a

The radiolabeling is carried out according to the procedure described in Example 13a.

Yttrium 90 ( ⁹⁰ YCl in HCl) is supplied by Perkin Elmer. The radiochemical purity is greater than 95%. Time Batch Radiochemical yield (%) Activity (MBq) Specific Activity (MBq/g) Volume activity (MBq/ml) 1H [90Y] T1H 96 226.6 157.7 201.9 24H 90Y] T3H 96 362.5 191.0 244.4 D3 90Y] T3J 96 350.6 159.5 204.2 J6 [90Y] T6J 98 343.6 172.1 220.2

The quality of the radiolabeling obtained for each test indicates that the protocol is reproducible. The robustness of this radiolabeling made it possible to produce batches of radiopharmaceuticals for in vivo studies. 56 female rats (Sprague-Dawley, aged 8 to 10 weeks, weighing between 220 and 225g, Janvier France) were acclimatized for 5 days (23°C, humidity 22%) with free access to food and drinking water.

Novikoff N1S1 cells (ATCC, UK) are used to induce hepatocellular carcinoma in rats.

Tumor induction consists of injecting N1S1 cells into rats according to the protocol described in the literature ( Garin E, Denizot B, Roux J et al. Description and technical pitfalls of a hepatoma model and of intra-arterial injection of radiolabeled Lipiodol in the rat. Lab Animals 2005; 39:314-320 ).

The radiolabeled complex of Example 13a is injected via a cannula (26G) previously inserted into the hepatic artery of the rat. The injected dose is approximately 3.5 Mbq.

The animals are sacrificed at 1 hour, 24 hours, 3 days and 6 days, the blood and the different organs are collected and weighed after dissection.

The tubes containing the organs are counted using a gamma counter (Perkin Elmer, USA) calibrated for yttrium 90.

The results are shown in the table below and in Figure 5 . 1H 24H 3D 6 days % dose injected into the tumor 29 ± 10 17 ± 10 23 ± 14 35 ± 18 Tumor/healthy liver dose ratio 5.4 ±2.6 3.3 ±1.9 4.9 ±3.4 8.5±4.8

Distribution of radioactivity in the liver

The study of biodistribution shows that the product according to the invention is well taken up by the tumor with a tumor/healthy liver ratio of at least 3 (see Figure 5 ), and that the dose captured by the healthy liver is low because it is approximately 5% of the injected dose. This selectivity of the distribution of the radioactive compound for the tumor makes it possible to consider its use in radiotherapy of liver tumors.

The same experiments were carried out with the compound of Example 13b (111 Indium). The results show that we find an injected tumor/healthy liver dose ratio greater than 5 at times of 1 hour and 6 days, which is consistent with the results observed for the compound of Example 13a. This selectivity of the distribution for the tumor of the radioactive compound of Example 13b makes it possible to envisage its use in radiotherapy of liver tumors.

The percentages of dose injected into the femur and bone marrow for the compounds of Example 13a and Example 13b, at 1 hour and 6 days after injection are in Figure 6 . These results show that the residual dose of radioactivity in these organs is extremely low (less than 0.05%). These results of low doses captured by these sensitive organs make it possible to consider the use of this compound in radiotherapy of liver tumors.

Claims (14)

1. Compound of the following general formula (I):

   

   in which R is a group of the following formula (II):
   
           -C≡C-Ph-L1-(CH2)n-L2     (II)
   
   with

   - L1 representing Ph or -C=C- or CH2,

   - L2 representing H or Ph or alkylphenyl,

   - n being between 4 and 12,

   or one of the pharmaceutically acceptable salts thereof.
2. Compound of formula (I) according to Claim 1, chosen from the group consisting of the following compounds:

   

   

   
3. Complex of a compound of formula (I) according to either one of the preceding claims, or one of the pharmaceutically acceptable salts thereof, with a chemical element M, M being a metal.
4. Complex according to Claim 3, wherein M is a radioelement chosen from the group consisting of ⁴⁴Sc(III), ⁴⁷Sc(III), ¹¹¹In(III), ¹⁵²Tb(III), ¹⁵⁵Tb(III), ¹⁴⁹Tb(III), ¹⁶¹Tb(III), ⁶⁴Cu(III), ⁶¹Cu(III), ⁶⁷Cu(II), ⁶⁸Ga(III), ⁹⁰Y(III), ¹⁵³Sm(III), ¹⁶⁶Ho(III), ¹⁷⁷Lu(III), ⁵²Mn and ²²⁵Ac(III), preferably ¹⁷⁷Lu(III), ⁹⁰Y(III), ²²⁵Ac(III), ⁶⁷Cu(II), ¹¹¹In(III), ¹⁵²Tb(III), ¹⁵⁵Tb(III), ¹⁴⁹Tb(III), ¹⁶¹Tb(III) and ⁶⁸Ga(III) .
5. Complex according to Claim 3 or 4, chosen from the group consisting of the following compounds:

   

   in which M is chosen from ¹⁷⁷Lu(III), ⁹⁰Y(III) and ¹¹¹In(III),

   

   in which M is ⁹⁰Y(III),
   and

   

   in which M is ⁹⁰Y(III).
6. Pharmaceutical composition comprising a compound according to either one of Claims 1 and 2, and optionally one or more pharmaceutically acceptable excipients; in particular the excipient is a radioprotector.
7. Pharmaceutical composition comprising a complex according to any one of Claims 3 to 5, and optionally one or more pharmaceutically acceptable excipients; in particular the excipient is a radioprotector.
8. Pharmaceutical composition according to Claim 6 or 7, further comprising an iodized oil, in particular an iodized oil comprising iodized ethyl esters of fatty acids of poppyseed oil.
9. Pharmaceutical composition according to Claim 8, comprising the following compound:

   

   or else comprising the following complex:

   

   in which M is preferably chosen from ¹⁷⁷Lu(III) and ⁹⁰Y(III).
10. Complex according to any one of Claims 3 to 5, for the use thereof in the treatment of cancers, in particular cancers of the liver.
11. Pharmaceutical composition according to one of Claims 6 to 9, for the use thereof in the treatment of cancers, in particular cancers of the liver.
12. Use of a complex according to any one of Claims 3 to 5, or of a pharmaceutical composition according to one of Claims 6 to 9, in medical imaging.
13. Process for preparing compounds of the following general formula (I):

    

    R being as defined in one of Claims 1 to 3, comprising a step of functionalizing a compound of the following general formula (IX):

    

    to form a compound of the following general formula (X):

    

    in which E2 is a C1-C4 alkyl protective group that can be chosen from the group consisting of methyl, ethyl, isopropyl and tert-butyl.
14. Process according to Claim 13, further comprising:

    - a step of deprotecting the compound of general formula (X) in order to obtain a compound of the following general formula (XI):

    

    and

    - a step of functionalizing the compound of general formula (XI) in order to obtain a compound of general formula (I):

    

    E1, E2 and E3 being C1-C4 alkyl protective groups that can for example be independently chosen from the group consisting of methyl, ethyl, isopropyl and tert-butyl.

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